Clinical prediction models assessing response to radiotherapy for rectal cancer: protocol for a systematic review.

BackgroundRectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol.MethodsIncluded studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted.Trial registrationCRD42022277704

Dose Escalation Using Contact X-ray Brachytherapy After External Beam Radiotherapy as Nonsurgical Treatment Option for Rectal Cancer: Outcomes From a Single-Center Experience

Purpose To review the outcomes of rectal cancer patients treated with a nonsurgical approach using contact x-ray brachytherapy (CXB) when suspicious residual disease (≤3 cm) was present after external beam chemoradiation therapy/radiation therapy (EBCRT/EBRT). Methods and Materials Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database. These patients were referred after initial local multidisciplinary team discussion because they were not suitable for, or had refused, surgery. All selected patients received a CXB boost after EBCRT/EBRT. Most patients received a total of 90 Gy of CXB delivered in 3 fractions over 4 weeks. Results The median follow-up period was 2.5 years (range 1.2-8.3). Of 345 consecutive patients with rectal cancer referred to us, 83 with suspicious residual disease (≤3 cm) after EBCRT/EBRT were identified for a CXB boost. Their median age was 72 years (range 36-87), and 58 (69.9%) were men. The initial tumor stages were cT2 (n = 28) and cT3 (n = 55), and 54.2% were node positive. A clinical complete response (cCR) was achieved in 53 patients (63.8%) after the CXB boost that followed EBCRT/EBRT. Of these 53 patients, 7 (13.2%) developed a relapse after achieving a cCR, and the 6 patients (11.6%) with nonmetastatic regrowth underwent salvage surgery (100%). At the end of the study period, 69 of 83 patients (83.1%) were cancer free. Conclusions Our data suggest that a CXB boost for selected patients with suspicious residual disease (≤3 cm) after EBCRT/EBRT can be offered as an alternative to radical surgery. In our series, patients with a sustained cCR had a low rate of local regrowth, and those with nonmetastatic regrowth could be salvaged successfully. This approach could provide an alternative treatment option for elderly or comorbid patients who are not suitable for surgery and those with rectal cancer who wish to avoid surgery

Dose escalation using contact X-ray brachytherapy (Papillon) for rectal cancer: does it improve the chance of organ preservation?

Objective: A watch and wait policy for patients with a clinical complete response (cCR) after external beam chemoradiotherapy (EBCRT) for rectal cancer is an attractive option. However, approximately one-third of tumours will regrow, which requires surgical salvage for cure. We assessed whether contact X-ray brachytherapy (CXB) can improve organ preservation by avoiding surgery for local regrowth. Methods: From our institutional database, we identified 200 of 573 patients treated by CXB from 2003 to 2012. Median age was 74 years (range 32–94), and 134 (67%) patients were males. Histology was confirmed in all patients and was staged using CT scan, MRI or endorectal ultrasound. All patients received combined CXB and EBCRT, except 17 (8.5%) who had CXB alone. Results: Initial cCR was achieved in 144/200 (72%) patients. 38/56 (68%) patients who had residual tumour received immediate salvage surgery. 16/144 (11%) patients developed local relapse after cCR, and 124/144 (86%) maintained cCR. At median follow up of 2.7 years, 161 (80.5%) patients were free of cancer. The main late toxicity was bleeding (28%). Organ preservation was achieved in 124/200 (62%) patients. Conclusion: Our data suggest that CXB can reduce local regrowth to 11% compared with around 30% after EBCRT alone. Organ preservation of 62% achieved was higher than reported in most published watch and wait studies. Advances in knowledge: CXB is a promising treatment option to avoid salvage surgery for local regrowth, which can improve the chance of organ preservation in patients who are not suitable for or refuse surgery

Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations

Background: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. Methods: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. Results: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73–88%) (four patients with clinical complete response declined surgery). Twenty–four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05–1.03, P=0.055). Conclusions: This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding: Cancer Research UK

Minimally invasive contact X-ray brachytherapy as an alternative option in patients with rectal cancer not suitable for bespoke surgical resection

Surgery remains the gold standard treatment for rectal cancer. All published guidelines and most protocols recommend surgery as the standard of care. However, non-surgical management of rectal cancer is increasingly gaining acceptance as it avoids extirpative surgery and a stoma. In patients who are not suitable for surgery because of advancing age or medical comorbidities, and also in a small number of patients who are stoma phobic and refuse surgery, we need to consider an alternative treatment option to bespoke surgery. External beam radiotherapy is usually offered as an alternative. However, local regrowth rate is high and contact X-ray brachytherapy (Papillon treatment) boost can be added to reduce the risk of local regrowth after external beam radiotherapy. Case selection is important to achieve the best results

Targeted Radiotherapy Using Contact X-ray Brachytherapy 50 kV

Rectal adenocarcinoma is a quite radioresistant tumor. In order to achieve non-operative management (NOM) radiotherapy plays a major role. Targeted radiotherapy aiming at high precision 3D radiotherapy uses stereotactic image-guided external beam radiotherapy machines. To further safely increase the tumor dose, endocavitary brachytherapy (ECB) is an original approach. There are two different ways to perform such an ECB: contact X-ray brachytherapy (CXB) using a 50 kV X-ray generator with an X-ray tube positioned under eye guidance into the rectal cavity and high-dose-rate brachytherapy (HDRB) using iridium-192 sources positioned into the rectal cavity under image guidance. This study focused on CXB. CXB uses a small mobile generator that produces 50 kV X-rays with limited penetration. This technique is well adapted to accessible tumors of limited size and especially needs a high dose rate (≥15 Gy/minutes) for rectal tumors. It is performed on an ambulatory basis. A total dose between 80–110 Gy is delivered in 3–4 fractions over 3 to 6 weeks into a small volume (5 cm3). CXB was pioneered in the 1970s by Papillon using the Philips RT 50TM. Since 2009, the Papillon P50TM has been used in 11 institutions in Europe. The OPERA Phase III trial tested the hypothesis that a CXB boost (90 Gy/3 fr) compared to an EBRT boost (9 Gy/5 fr) for T2–T3 ab TM, organ preservation appears possible in close to 80% of cases in selected early T2–T3. The OPERA trial closed after 141 inclusions (2015–2020) after an independent data monitoring committee recommendation because of promising results. At the 2-year follow-up (blinded data), the rate of cCR and OP were 77% and 72%, respectively, for the 141 tumors, and for T < 3 cm (61 pts), they were 86% and 85%, respectively, with good bowel function. The final results should be available in 2022. Organ preservation using NOM appears to be a promising approach for rectal cancer. A CXB boost with chemoradiotherapy in selected early T2–T3 could become an attractive option to achieve a planned OP. This approach should be proposed to well-informed patients after discussion in an MDT